EP1049451B1 - Verwendung von verbindungen zum schutz der haut gegen uv-induzierter immunsuppression - Google Patents

Verwendung von verbindungen zum schutz der haut gegen uv-induzierter immunsuppression Download PDF

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Publication number
EP1049451B1
EP1049451B1 EP98960911A EP98960911A EP1049451B1 EP 1049451 B1 EP1049451 B1 EP 1049451B1 EP 98960911 A EP98960911 A EP 98960911A EP 98960911 A EP98960911 A EP 98960911A EP 1049451 B1 EP1049451 B1 EP 1049451B1
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Prior art keywords
skin
equol
glucan
compounds
compositions
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French (fr)
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EP1049451A4 (de
EP1049451A1 (de
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Graham Edmund Kelly
Alan James Husband
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Kazia Research Pty Ltd
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Novogen Research Pty Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/004—Aftersun preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • This invention relates to the use of certain compounds and compositions thereof in the manufacture of a medicament for the treatment, amelioration, prophylaxis and/or prevention of skin from UV-induced immunosuppression, such as resulting from exposure to the sun.
  • Exposure of the skin to ultraviolet radiation causes both critical damage to the epidermal DNA, which may have long-term irreversible consequences if remaining unrepaired, and may lead to a specific impairment of the T lymphocyte immune system.
  • the immuosuppression caused by UV exposure appears to be a prerequisite for non-melanoma and melanoma cancer promotion. It is mediated by a number of mechanisms, such as the formation of epidermal cis -urocanic acid in UV-irradiated skin, the persistence of pyrimidine dimers in epidermal DNA, and the upregulation ofinflammatory eicosanoids like PGE2. It is understood that photoimmunosuppression permits the initiated tumour cell to evade recognition and rejection by normal immunological mechanisms, to remain latent for extended periods, and to eventually proliferate into a tumour.
  • the chronic exposure of the skin to solar radiation is well documented as the cause of the photoageing phenomenon, such as thickening of skin, drying of skin, increased skin pigmentation, skin spots and skin lesions.
  • UV exposure such as chronic solar UV radiation causes the well known effects of reddening of the skin with accompanying inflammation, known as erythema. This is often referred to as "sunburn” which is painful, often itchy, and generally results in a subsequent peeling of the skin which has been subject to chronic solar irradiation.
  • Erythema is particularly prevalent in light skinned individuals and children. Chronic erythema may predispose individuals to skin disorders, such as skin cancers in later life. Depending on an individual's skin colouration, erythema may result in as little as 20 minutes exposure to the sun.
  • sunscreen compositions contain UVA-type sunscreen agents and/or UVB-type sunscreen agents.
  • Typical UVA-type sunscreen agents include certain benzophenones and dibenzylmethanes.
  • Typical UVB-type sunscreen agents include substituted para-aminobenzoates, alkyl esters of para-methoxycinnamate and/or various esters of salicylic acid.
  • sunscreening agents are used in amounts effective to provide the desired level of protection from erythema caused by UVA and/or UVB radiation. Examples of many known sun screening agents are described in WO 96/14826.
  • Sun screening compositions may contain physical sun screening agents such as red petrolatum, or titanium dioxide, such as in amounts from 2-5% by weight of the total composition. Precipitated silica, kaolin, talc, chalk and the like may also be used in such compositions.
  • compositions of the prior art and in particular based on isoflavones are used to treat UV-induced skin damage.
  • DE 4432947 A describes compositions comprising isoflavones and their uses for skin treatment, in particular in the cosmetic and medical fields, such as acne, rosacea, melanoma, alopecia and depigmentation.
  • WO 97/46208 is related to a method of inhibiting the harmful effects of UV exposure to the human skin comprising topically applying a therapeutically effective amount of genistein to the skin at a time sufficiently close to the time of UV exposure to inhibit UV-induced skin damage to the skin, in particular UV-induced skin photodamage and skin cancer.
  • Such a method inhibits skin erythema in human subjects and the mRNA expression of proto-oncogenes c-fos and c-jun in mice after UV exposure.
  • JP 60061513 A discloses compositions containing 5-hydroxyisoflavones, preferably genistein or genistin, and their use in cosmetic compositions as anti-sunbum agents and to promote skin-smoothing effects.
  • JP 07017847 A discloses external preparations containing and active substance namely kojic acid and/or its derivatives and one or more extracts of various origin, among which clover extract is listed. It also discloses that said preparations are used as cosmetics for skin-refreshment wrinkle prevention.
  • EP 0201956 A is related to antioxidant compositions prepared by the extraction of natural antioxidants from plant substrates and methods related to the use thereof as cosmetics, food preservation or therapeutic purposes. For example, a method of cosmetically enhancing the texture of the skin consisting in the use of a soluble antioxidant derived from plant tissues, which is capable of being absorbed into mammalian skin where it reduces the peroxide level is disclosed.
  • antioxidant compositions according to EP 0201956 A can be used to protect the skin from UV radiation-induced damage or to inhibit tumor development and in particular skin cancer such as melanoma.
  • WO 93/23069 discloses compositions enriched with genistein, diadzein, formononetin and biochanin A for promoting health in cases of cancer, premenstrual syndrome, menopause or hypercholesterol.
  • WO 98/08503 discloses certain isoflavone compounds and use thereof in the treatment, prophylaxis and/or prevention of menopausal syndrome including hot flushes, anxiety and depression, mood swings, night sweats, headaches, urinary incontinence, osteoporosis, premenstrual syndrome, including fluid retention, cyclic mastalgia and dysmenorrhoea; Reynauld's syndrome, Reynaud's Phenomenon; Buergers Disease, coronary artery spasam, migraine headaches, hypertension, benign prostatic hypertrophy, breast cancer, uterine cancer, ovarian cancer, testicular cancer, atherosclerosis, Alzheimers disease, inflammatory diseases including inflammatory bowel disease, ulcerative colitis, Crohns Disease, rheumatic diseases including rheumatoid arthritis, acne, baldness including male pattern baldness; psoriasis and diseases associated with oxidant stress including cancer, myocardial infarction
  • WO 96/28476 discloses a process for the production of ⁇ -(1,3)(1,6)-glucan from a glucan containing cellular source, together with uses/methods of treatment involving glucan including use in the treatment of skin ulceration or bone fractures.
  • the invention provides use of a compound selected from the group consisting of equol, dehydroequol and clover extract or a combination of compounds selected from the group consisting of genistein and ⁇ -(1,3)(1,6)-glucan, equol and ⁇ -(1,3)(1,6)-glucan and clover extract and ⁇ -(1,3)(1,6)-glucan for the manufacture of a medicament for the treatement, amelioration, prophylaxis and/or prevention of skin from UV induced immunosuppression.
  • Such a medicament can be a topical or oral medicament.
  • the medicament comprises a pharmaceutically acceptable carrier.
  • the invention also provides use of a composition
  • a composition comprising a compound selected from the group consisting of equol, dehydroequol and clover extract or a combination of compounds selected from the group consisting of genistein and ⁇ -(1,3)(1,6)-glucan, equol and ⁇ -(1,3)(1,6)-glucan and clover extract and ⁇ -(1,3)(1,6)-glucan for for the manufacture of a composition for the treatment, amelioration, prophylaxis and/or prevention skin from UV induced immunosuppression.
  • Such a composition can comprise a dermatologically acceptable carrier, and is preferably a topical composition.
  • compositions of the present invention do not include a UV absorber or a plurality of UV absorbers added for the purpose of protecting against UV irradiation. Nor do the compositions of this invention include any stabilizing compounds which provide UV stability or other stability to UV absorbing compounds given the absence of such compounds from the compositions of the present invention.
  • Dermatologically acceptable carriers are those which are compatible with the skin and can be readily applied to the skin by standard means. Components of such carriers include, but are not limited to, one or more of water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, and mineral oils. Dermatologically acceptable carriers may be in the form of lotions, creams, gels, mousses, aqueous liquids of varying viscosity, waxed based sticks, aerosols, alcohol sticks and the like. Examples of formulations well known in the art may be found in Balsam, M. S. and Sagrin, E. (editors) Cosmetic Science and Technology, second edition, Volume 1 and 2, Wiley-Interscience, a division of John Wiley & Sons Inc, New York, 1972 and Flick, E. W. Cosmetic and Toiletry Formulations, Noyse Publications 1984.
  • Dermatologically acceptable carriers may include one or more emollients, emulsifiers, surfactants, waxes, thickeners, film formers, preservatives and perfumes.
  • emollients such as, but not limited to, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethacrylate, ethylene glycol dimethoxymethyl methoxylate, steaditol, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stevia, stearic acid, sulfate, ethylene glycol dimeth
  • An example of the standard lotion for topical application to the skin contains the following: paraffin oil bees wax triethanolamine olive oil glyceryl monostearate anhydrous lanolin oleic acid stearic acid water
  • the components listed above, other than water, may be present in an amount from about 0.01% to 10% w/w.
  • Water may be present in an amount from about 20% to about 90% w/w.
  • Compounds employed in the invention may be present in such a lotion in an amount from 0.05% to 10% w/w.
  • compositions used according to the present invention may be readily prepared according to standard procedures known in the art for the preparation of compositions for topical application to the skin, for example as described by Balsam, M. S. and Sagrin, E. (editors) Cosmetic Science and Technology, second edition, Volume 1 and 2, Wiley-Interscience, a division of John Wiley & Sons Inc, New York, 1972 and Flick, E. W. Cosmetic and toiletry Formulations, Noyse Publications, 1984.
  • compositions may be prepared by blending together the compounds employed in the invention (optionally dissolved in a solvent such as DMSO, ethanol, paraffin oil, olive oil or other suitable solvents) and one or more dermatological acceptable carriers, such as first by dissolving.
  • the carrier may be a solid or a liquid, or both and is preferably formulated with compounds employed in the invention as a unit dose, for example, a tablet, which may contain from 0.5% to 60% by weight of the active component.
  • One or more active compounds may be formulated with one or more carriers by well known techniques of pharmacy. Formulations may be prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier or both, and then, if necessary, shaping the resulting mixture to form a unit dosage.
  • Moulded tablets may, for example, be made by moulding together powdered components moistened with an inert liquid binder.
  • Compositions may be administered before and/or after UV exposure.
  • Conveniently compositions are administered daily, for example giving a daily administration of 0.05 mg to 500 mg per day of active components.
  • Compounds employed in the invention may be prepared according to procedures disclosed in WO 98/08503. Compounds employed in the invention may be purified from human urine according to the procedures of Jaonnou et al (1995) J. Steroid. Biochem. Molec. Biol., 54, 167-184.
  • Extracts of soy or clover may be prepared according WO93/23069. As described in WO93/23069 soy or clover may be extracted with a mixture of organic solvent (such as ethanol, chloroform, acetone, ethyl acetate and the like) and water. The ratio of solvent in water may be from 0.1 % to 99.9%, preferably 40% to 60%.
  • organic solvent such as ethanol, chloroform, acetone, ethyl acetate and the like
  • Red clover T. pratense
  • subterranean clover T. subterranean
  • Red clover T. pratense
  • subterranean clover T. subterranean
  • Raw plant material may be dried, chaffed or otherwise comminuted and then subject to extraction.
  • the resultant organic solvent layer following extraction is removed such as by distillation, and the aqueous layer and residual material from the organic layer concentrated as desired, such as by distillation.
  • beans may be treated to remove the hull (such as by using a tumble mill which splits the beans into two cotyledons and a hypocotyl which may be separated from one another).
  • Cotyledons, and optionally hypocotyls may be comminuted and then subject to extraction as described above. Extracts may include one or more compounds employed in the invention.
  • Extracts are formulated with a dermatologically acceptable carrier as herein described to give a composition for application to the skin, or formulated for oral administration.
  • Compositions may contain from 0.01% to 10% w/w of extract.
  • composition of the present invention includes ⁇ -(1-3)(1 ,6)-glucan (such as prepared according to WO 96/28476), it may be present in an amount from 0.1% to 30% w/w. If particulate, the glucan may be dissolved in 0.1 % DMSO or other suitable dissolving solvent. Such compositions may exhibit synergism between the respective components resulting in highly potent protection from UV induced skin damage.
  • UV induced skin damage refers to any sunlight or other UV damage which effects skin, whether of a human or animal. Such damage includes erythema (reddening and swelling of the skin, often referred to as sunburn) photoaging of skin such as hyperkeratinization and elastosis and skin lesions such as precancerous and cancerous lesions, for example actinic keratoses and pre-malignant and malignant skin cancers.
  • erythema reddening and swelling of the skin, often referred to as sunburn
  • skin lesions such as precancerous and cancerous lesions, for example actinic keratoses and pre-malignant and malignant skin cancers.
  • the use of the compounds for protecting skin against UV induced immunosuppression according to the invention comprises orally administering to a subject either before and/or after UV exposure the compounds employed in the invention.
  • Compositions are applied to the skin following sun exposure, and are generally applied after each exposure to the skin, or alternatively at the end of a day following a series of exposure of the skin to sun.
  • compositions may be applied to the skin by any convenient means known in the art, such as by way of being rubbed on, rolled on, sprayed on, wiped on or the like.
  • the mode of application would generally depend upon the nature of the formulation, whether a cream, foam, lotion, roll-on "stick", liquid of varying viscosity, or the like.
  • a standard model for testing immunosuppression that is a model with reference to human immunosuppression, is the hairless mouse.
  • a standard test in the hairless mouse model is the contact hypersensitivity (CHS) reaction to an immune irritant such as oxazolone (Asherson and Ptak, Immunology, (1968) 15:405-416).
  • CHS contact hypersensitivity
  • oxazolone an immune irritant
  • the compound oxazolone induces a vigorous immune response in the hairless mouse which may be measured by ear swelling. Immune suppression by UV light or other agents can be readily tested in the model.
  • compositions comprising compounds employed in the invention were active in the treatment/prevention/amelioration ofUV induced immunosuppression in the hairless mouse model, which as discussed above is directly referable to the situation in human skin, for example, Yoshikawa et al, J. Invest. Dermatol., 95:530-536, (1990).
  • Hairless mouse strains such as the HRA-Skh-1 mice are a standard mouse model used to study solar damage to human skin [Canfield et al, Pathology, 17:613-616, (1985)]. Exposure of the hairless mouse to UV light mimics "sunburn" in humans. With continued irradiation treatment, this on-going damage is reflected in progressive thickening of the skin which histologically mimics hyperkeratinization and elastosis associated with photoaging and chronically sun-exposed skin in humans. Pre-malignant tumours begin to appear with several weeks of completion of the ultra violet light regimen. Over an ensuing time period there is a progressive development of pre-malignant and malignant tumours, the histology and behaviour of which closely mimic actinic keratoses and pre-malignant and malignant skin cancers that develop in humans in response to sunlight.
  • a lotion (“base or test lotion”) was prepared by mixing together the following components: ml ml paraffin oil 80 glyceryl monostearate 60 olive oil 60 oleic acid 25 anhydrous lanolin 60 water 1200 stearic acid 58 triethanolamine 27 beeswax 10
  • DMSO dimethylsulfoxide
  • Test lotion "A” was prepared containing 20 ⁇ M of various compounds employed in the invention dissolved in 0.1% DMSO (a primary solvent for the compounds).
  • Test lotion 'B' was prepared containing 20 ⁇ M of various compounds employed in the invention dissolved in 0.1 % DMSO in combination with a solution of ⁇ (1,3)(1,6)-glucan (10% w/w).
  • An extract of red clover was prepared according to WO93/23069.
  • the aqueous extract, or a particulate or dried extract dissolved in 0.1 % DMSO is incorporated into the base lotion in an amount of 0.5% w/w.
  • mice The CHS reaction in mice is a standard model for immunosuppression and is a representative model for human immunosuppression (Yoshikawa et al, Invest. Dermatol., 95:530-536 (1990)).
  • the CHS reaction was carried out according to the protocol of Reeve et al, Immunology, 78:99-104 (1993). Hairless albino Sh:HR-1 mice were divided into two treatment groups.
  • the first treatment group designated group 1 was not subject to UV irradiation, and received either 0.2 ml of test lotion "A" or test lotion 'B' painted on to the dorsal skin on four consecutive days (that is, 4 ⁇ mol/mouse, or approximately 0.1 ⁇ mol/cm 2 ).
  • the second treatment group, group 2 were UV irradiated with a minimal erythemal dose of UV light which simulates the toxic effect of sunlight on the skin. After each daily UV treatment 0.2 ml of treatment solution was applied to the dorsal skin as for treatment group 1.
  • Mid-dorsal skinfold thickness was measured every twenty four hours to indicate erythema oedema.
  • CHS to oxazolone was induced on abdominal skin seven days after the first treatment followed by challenge on the ears on day 15, and average ear swelling was determined as a measure of immune response.
  • Genistein, daidzein, equol, tetrahydrodaidzein, ODMA (O-desmethyl-angolensin), dehydroequol and clover extract were tested in this experiment in test lotion "A". Equol, genistein and clover extract were also tested in tes lotion 'B'. The results expressed below are given as a percentage of suppression of CHS measured with reference to the non-UV exposed treatment group 1, which is induced by UV exposure.
  • Results are as follows: Hours of ear challenge % Suppression of CHS 18 21 Base lotion 24 37 Genistein 14 13 Daidzein 27 37 Equol 12 5 tetrahydrodaidzein 33 31 dehydroequol 10 4 Clover extract 8 9 Genistein and glucan 11 9 Equol and glucan 8 3 Clover extract and glucan 5 5
  • Erythema/oedema was measured at day four and day seven of the treatment groups. These results show that genistein and equol suppressed erythema/oedema. For example, at seven days after treatment for base lotion "A" average skin fold thickness was six units (that is 0.006 in), for the daidzein containing lotion average skin fold increase was seven units, and for tetrahydrodaidzein average skin fold thickness was five units. In contrast, for equol, genistein, dehydroequol and ODMA there was a negative average skin fold increase of approximately 0.2, which corresponds to substantially no increase in skin fold thickness. This result shows that compositions containing compounds employed in the invention are effective in protecting against UV induced skin damage, particularly erythema, oedema, and thickening of the skin.
  • Tests were performed at the Australian Photobiology Testing Facility at the University of Sydney. Human subjects were tested in a controlled solarium. A grid was established using reference coordinate points on the back of each subject, thereby providing a series of treatment sites on the back of each patient where the erythema-reducing potential of compositions according to the invention could be tested.
  • Equol was dissolved in DMSO and incorporated into base lotion "A" to contain 100 ⁇ M of active ingredient, and 0.5% DMSO.
  • Topical applications were made to the back of the patient within the treatment grid which was established to provide a series of sites for UV irradiation, and subsequent application of compositions.
  • Topical application consisted of 2 mg/cm 2 lotion applied firmly, followed by a second 2 mg/cm 2 applied but not rubbed in. Each topical treatment was therefore 0.4 nmols/cm 2 equol.
  • the treatment procedure was as follows. On the first day of treatment a minimum erythemal dose of UV (MED) was established for each subject, this being the minimum degree of UV light which on visual determination produces a reddening of the skin. From this data, which is specific for each patient, a 0.75 level of minimum erythema dose was calculated (0.75 x MED). The first treatment day was a Monday. Subsequent treatments were as follows:
  • compositions containing equol can be used in therapeutic treatment to prevent UV damage after sun exposure in humans.
  • mice On days 7 and 8 the mice were sensitised with 2% oxazolone in alcohol (100ul/mouse). On day 14, the ears were challenged with 2% oxazolone (20ul/mouse). On day 15, the ears were measured for skin fold thickness and suppression of chronic hypersensitivity. The results indicated that both glucan and equol were effective in decreasing the percentage suppression of chronic hypersensitivity and skin fold thickness, and that in combination they provided potentiated protection when compared to the control groups. Lotion % Suppression of CHS Difference in skin fold thickness from day 1 (mm) Base lotion only 41% 47.7 Glucan only 4.5% 25 Equol only 6% 29.8 Glucan + equol 2.5% 16.8

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Claims (7)

  1. Verwendung einer Verbindung ausgewählt aus der Gruppe bestehend aus Equol, Dehydroequol und einem Klee-Extrakt oder einer Kombination von Verbindungen ausgewählt aus der Gruppe bestehend aus Genistein und β-(1,3)(1,6)-Glucan, Equol und β-(1,3)(1,6)-Glucan, Klee-Extrakt und β-(1,3)(1,6)-Glucan zur Herstellung eines Medikamentes zur Behandlung, Verbesserung, Prophylaxe und/oder Prävention einer durch UV-Strahlung induzierten Immunosuppression der Haut.
  2. Verwendung gemäß Anspruch 1, wobei es sich bei dem Medikament um ein topisches Medikament handelt.
  3. Verwendung gemäß Anspruch 1, wobei es sich bei dem Medikament um ein orales Medikament handelt.
  4. Verwendung gemäß irgendeinem der Ansprüche 1 bis 3, wobei das Medikament einen pharmazeutisch akzeptablen Träger enthält.
  5. Verwendung einer Zusammensetzung enthaltend eine Verbindung ausgewählt aus der Gruppe bestehend aus Equol, Dehydroequol und einem Klee-Extrakt oder eine Kombination von Verbindungen ausgewählt aus der Gruppe bestehend aus Genistein und β-(1,3)(1,6)-Glucan, Equol und β-(1,3)(1,6)-Glucan, Klee-Extrakt und β-(1,3)(1,6)-Glucan zur Herstellung einer Zusammensetzung zur Behandlung, Verbesserung, Prophylaxe und/oder Prävention einer durch UV-Strahlung induzierten Immunosuppression der Haut.
  6. Verwendung gemäß Anspruch 5, wobei die Zusammensetzung einen dermatologisch akzeptablen Träger enthält.
  7. Verwendung gemäß Anspruch 6, wobei es sich bei der Zusammensetzung um eine topische Zusammensetzung handelt.
EP98960911A 1997-12-24 1998-12-21 Verwendung von verbindungen zum schutz der haut gegen uv-induzierter immunsuppression Expired - Lifetime EP1049451B1 (de)

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WO1999036050A1 (en) 1999-07-22
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ATE311171T1 (de) 2005-12-15
DE69832637D1 (de) 2006-01-05
US20030059384A1 (en) 2003-03-27
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MXPA00006311A (es) 2002-08-20
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CA2316349C (en) 2009-12-15
DE69832637T2 (de) 2006-07-27
NO20003201L (no) 2000-08-22
US6455032B1 (en) 2002-09-24
US20050036962A1 (en) 2005-02-17
ES2253838T3 (es) 2006-06-01
AUPP112497A0 (en) 1998-01-22
DK1049451T3 (da) 2006-04-10
CA2316349A1 (en) 1999-07-22
IL136784A0 (en) 2001-06-14
SE0002286D0 (sv) 2000-06-19
NZ505377A (en) 2003-05-30
EP1049451A4 (de) 2001-04-11
BR9814343A (pt) 2004-04-13
TR200002064T2 (tr) 2001-01-22
EP1049451A1 (de) 2000-11-08

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